Neurological and Endocrine Toxicology Branch, PHITD, CPHEA, ORD, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Oak Ridge Institute for Science and Education Research Participation Program, U.S. Department of Energy, Oak Ridge, TN 37831, USA.
Int J Mol Sci. 2023 Mar 29;24(7):6404. doi: 10.3390/ijms24076404.
Exposure to a prototypic air pollutant ozone (O) has been associated with the activation of neuroendocrine stress response along with neural changes in oxidative stress (OS), inflammation, and Alzheimer's disease-like pathologies in susceptible animal models. We hypothesized that neural oxidative and transcriptional changes induced by O in stress responsive regions are sex-dependent. Male and female adult Long-Evans rats were exposed to filtered air or O for two consecutive days (0.8 ppm, 4 h/day) and brain regions were flash-frozen. Activities of cerebellar OS parameters and mitochondrial complex I, II, and IV enzymes were assessed to confirm prior findings. We assessed transcriptional changes in hypothalamus (HYP) and hippocampus (HIP) for markers of OS, microglial activity and glucocorticoid signaling using qPCR. Although there were no O or sex-related differences in the cerebellar activities of OS and mitochondrial enzymes, the levels of protein carbonyls and complex II activities were higher in females regardless of O. There were no statistical differences in baseline expression of genes related to OS (, , , , , , ) except for lower HYP expression in air-exposed females than males, and higher HIP expression in O-exposed females relative to matched males. Microglial marker expression was higher in O-exposed females relative to males; O inhibited only in males. The expression of in HIP and HYP was inhibited by O in both sexes. Genes related to glucocorticoid signaling (, , , , , ) showed sex-specific effects due to O exposure. Baseline expression of HIP was higher in females relative to males. O inhibited Nr3c1 in female HIP and male HYP, but was inhibited in male HYP. expression was higher in O-exposed females when compared to matched males, whereas was expressed at higher levels in both brain regions of males and females. These results indicate that sex-specific brain region responses to O might, in part, be caused by OS and regulation of glucocorticoid signaling.
暴露于原型空气污染物臭氧 (O) 已与神经内分泌应激反应的激活以及氧化应激 (OS)、炎症和阿尔茨海默病样病理学的神经变化相关，在易感动物模型中也是如此。我们假设，O 在应激反应区域引起的神经氧化和转录变化是具有性别依赖性的。雄性和雌性成年长爪沙鼠分别暴露于过滤空气或 O 中连续两天（0.8 ppm，4 小时/天），然后将大脑区域迅速冷冻。评估小脑 OS 参数和线粒体复合物 I、II 和 IV 酶的活性以确认先前的发现。我们使用 qPCR 评估下丘脑 (HYP) 和海马 (HIP) 中 OS、小胶质细胞活性和糖皮质激素信号的标志物的转录变化。尽管小脑 OS 和线粒体酶的活性或性别之间没有 O 或性别相关的差异，但无论 O 如何，雌性的蛋白质羰基和复合物 II 活性水平都更高。除了暴露于空气中的雌性 HYP 比雄性 HYP 的表达水平更低，以及暴露于 O 中的雌性 HIP 的表达水平比匹配的雄性更高之外，与 OS 相关的基因的基线表达（ ， ， ， ， ， ）没有统计学差异。HYP 和 HIP 中的 表达在 O 暴露的雌性中相对雄性更高；O 仅在雄性中抑制 。在 O 暴露的雌性中，小胶质细胞标志物 表达高于雄性；O 抑制 HIP 和 HYP 中的 。O 抑制了两性中的 表达。与糖皮质激素信号相关的基因（ ， ， ， ， ， ）由于 O 暴露而表现出性别特异性效应。HIP 的基线表达在雌性中高于雄性。O 抑制了雌性 HIP 和雄性 HYP 中的 Nr3c1，但抑制了雄性 HYP 中的 。与匹配的雄性相比，暴露于 O 中的雌性的 表达更高，而 表达在两性的两个大脑区域中均更高。这些结果表明，O 对大脑区域的性别特异性反应可能部分归因于 OS 和糖皮质激素信号的调节。
